08: Neuroscience Using Yeast Cells To Define Mechanisms of Human Neurodegenerative Diseases The United States and other countries around the world are experiencing a demographic sea change owing to the rapidly growing elderly and 'Baby Boomer' populations. As our population continues to age, neurodegenerative disease will increase in prevalence and thus pose a daunting challenge to public health worldwide. These truly disastrous disorders include Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis and the frontal temporal dementias. Interestingly, though disparate in their pathophysiology, many of these diseases share a common theme manifest in the accumulation of insoluble protein aggregates in the brain. The long-term goal of my laboratory is to elucidate the mechanisms causing these proteins to misfold and aggregate, identify the genes and cellular pathways affected by misfolded human disease proteins, and understand their function in normal biology. We are taking an innovative approach to attacking this exceedingly difficult problem: harnessing the baker's yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms underpinning protein-misfolding diseases. Surviving cellular stresses caused by misfolded proteins is an ancient problem that all cells struggle with and many of the mechanisms employed to deal with protein misfolding are conserved from yeast to man. We propose to create yeast models of human neurodegenerative diseases and to perform high-throughput genome-wide screens to elucidate the basic cellular mechanisms of toxicity. These yeast models will provide us with a unique opportunity to observe and understand protein folding and misfolding in real time as it occurs in a living cell and then to ask big questions on a genome- wide scale about the cellular pathways affected by the aberrant accumulation and/or function of human disease proteins. We hypothesize that the mechanisms identified by our studies will have broad applicability to multiple neurodegenerative diseases. The innovative aspect of our approach is not just that we are working in yeast, but that we are willing and able to use this system as a discovery tool, which we will validate in more relevant animal models. We have done this successfully in the past (via collaboration and on our own) and this will allow us to proceed with future experiments from a knowledgeable point of view, knowing the relative strengths of various organisms and methods.